title: microRNA-22 promotes heart failure through coordinate suppression of PPAR/ERR-nuclear hormone receptor transcription.
abstract: Increasing evidence suggests that microRNAs are intimately involved in the pathophysiology of heart failure. MicroRNA-22 (miR-22) is a muscle-enriched miRNA required for optimum cardiac gene transcription and adaptation to hemodynamic stress by pressure overload in mice. Recent evidence also suggests that miR-22 induces hypertrophic growth and it is oftentimes upregulated in end stage heart failure. However the scope of mRNA targets and networks of miR-22 in the heart failure remained unclear. We analyzed transgenic mice with enhanced levels of miR-22 expression in adult cardiomyocytes to identify important pathophysiologic targets of miR-22. Our data shows that forced expression of miR-22 induces a pro-hypertrophic gene expression program, and it elicits contractile dysfunction leading to cardiac dilation and heart failure. Increased expression of miR-22 impairs the Ca(2+) transient, Ca(2+) loading into the sarcoplasmic reticulum plus it interferes with transcription of estrogen related receptor (ERR) and PPAR downstream genes. Mechanistically, miR-22 postranscriptionally inhibits peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), PPARα and sirtuin 1 (SIRT1) expression via a synergistic circuit, which may account for deleterious actions of unchecked miR-22 expression on the heart.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Priyatansh
authors.initials: P
authors.lastname: Gurha
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Larimore
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.forename: Cei
authors.initials: C
authors.lastname: Abreu-Goodger
authors.forename: Maricela O
authors.initials: MO
authors.lastname: Ramirez
authors.forename: Anilkumar K
authors.initials: AK
authors.lastname: Reddy
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Antony
authors.initials: A
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology; D015151:Immunoblotting; D008156:Luciferases; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D047492:Peroxisome Proliferator-Activated Receptors; D011960:Receptors, Estrogen; D008156:Luciferases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002118:Calcium